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Division of Animal Clinical Chemistry Regulatory Issues

REGULATORY UPDATE – July 2008

FDA and EMEA Approve Acceptance Of Seven New Biomarkers In Urine for Assessment of Renal Toxicity

New Methods Are Considered As Qualified For Use In Drug Development

In June 2008, the FDA released an announcement of their joint review (with the EMEA) and acceptance of seven new preclinical laboratory tests on urine which signal kidney injury. These protein signals/biomarkers were confirmed in data from rat studies submitted to the FDA and EMEA by the Predictive Safety Testing Consortium (PSTC). The news release, in part, is presented below for your attention and review. There are 17 corporate members of the consortium which share internally developed pre-clinical safety biomarkers in five workgroups: carcinogenicity, kidney, liver, muscle and vascular injury. The results of the characterization of (new) biomarkers of drug-induced kidney injury are now encouraged and accepted by the agencies in support of preclinical safety assessment. Many of you have already heard some discussion of these new biomarkers and have begun to evaluate the impact on clinical pathology operations. To others this represents a new hot topic for your attention, and for all of us it presents a learning curve as clinical pathology applications and interpretations continue to expand.

“In the first use of a framework allowing submission of a single application to the two agencies, the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) worked together to allow drug companies to submit the results of seven new tests that evaluate kidney damage during animal studies of new drugs. The tests measure the levels of seven key proteins or "biomarkers" found in urine that can provide additional information about drug-induced damage to kidney cells, also known as renal toxicity.

The new biomarkers are KIM-1, Albumin, Total Protein, β2-microglobulin, Cystatin C, Clusterin, and Trefoil Factor-3. For decades, both FDA and EMEA have required drug companies to submit the results of two blood tests, called blood urea nitrogen (BUN) and serum creatinine, to evaluate renal toxicity. In addition to those tests, the FDA and EMEA will now consider results from the seven new tests as part of their respective drug review processes. Although a decision by the sponsor to collect information using the new tests is voluntary, if collected, it must be submitted to FDA.

"The development of these and other biomarkers can result in important tools for better understanding the safety profile of new drugs," said Janet Woodcock, M.D., director of FDA's Center for Drug Evaluation and Research. "We hope these biomarkers will lead to human tests that detect drug-induced kidney injury in people earlier than is now possible, and help health care professionals better manage potential kidney damage from drugs."

Woodcock added that such human tests could one day open the door to the approval of more powerful drugs, especially for diseases where renal toxicity currently prevents promising experimental drugs from being approved. With more sensitive tests for renal toxicity, FDA could approve such drugs because health care professionals could closely monitor patients and halt the drug if early signs of renal toxicity appear.

Development of the new biomarkers was led by the Predictive Safety Testing Consortium (PSTC), whose members include scientists from 16 pharmaceutical companies. The PSTC was organized and led by the Critical Path Institute, a nonprofit organization that works to support FDA research collaborations that improve the development of medical products.

Researchers from Merck & Co., Whitehouse Station, N.J., and Novartis AG, Basel, Switzerland, identified the new biomarkers, tested them to prove their accuracy and usefulness, and then shared their findings with the other consortium members for further study. The consortium then submitted applications for use of the biomarkers to FDA and EMEA.

The project is the first in which a group of drug companies has worked together to propose and qualify new safety tests and then present them jointly to the FDA and EMEA for consideration. The FDA and EMEA laid the groundwork for these specific joint-agency biomarker reviews in 2004 when they developed a framework called the Voluntary Exploratory Data Submission review process.

The new process allowed the PSTC to submit a single biomarker data application to both regulatory agencies, and then to meet jointly with scientists from both agencies to discuss it in detail and to address additional scientific questions posed by the regulators. Each regulatory agency then reviewed the application separately and made independent decisions on use of the new biomarkers.

FDA scientists believe that the seven new tests may provide important advantages over the BUN and creatinine tests. For example, in experiments using rats, the two traditional tests can only detect kidney damage a week after it has begun to occur. The new tests, however, are more sensitive and can detect cellular damage within hours. And while BUN and serum creatinine show that damage has occurred somewhere in the kidneys, the new tests can pinpoint which parts of the kidney have been affected.

The seven new tests were developed and will be carried out initially in rats. These tests were selected because other studies have shown that identical biomarkers are produced in human kidney cells. While the FDA and EMEA will consider these biomarkers in rat studies initially, the PSTC has begun work to further qualify the biomarkers for use in human studies. If successful, the PSTC will present a new biomarker data application to the two agencies to seek acceptance of the human biomarkers.”

For your additional information: some Links to the Predictive Safety Testing Consortium and FDA and EMEA announcements are -

Although this announcement specifically relates to new markers for preclinical assessment of nephrotoxicity and its translation to clinical programs, we need to be alert that similar activities are underway for preclinical safety biomarkers in the other workgroups for carcinogenicity, liver, muscle and vascular injury. Thus, it is recommended that you inform yourselves and your colleagues as much as possible to plan to best satisfy compliance across your organizations.

JP Kimball
DACC Regulatory Affairs/Intersociety Liaison

Regulatory Update - October 2004

Title 21 CFR – DRAFT Guidance Document Released

The FDA has distributed a Title 21 CFR ‘Guidance for Industry - Computerized Systems Used in Clinical Trials” as a draft guidance for comment purposes as of September 2004. A 90 day period for submission of comments and suggestions regarding this draft document is in force subsequent to publication in the Federal Register of the notice announcing the availability of the draft guidance. Comments should be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

Below are selected excerpts from the new guidance for your information.

Title 21 CFR , Guidance for Industry

Computerized Systems Used in Clinical Trials

September 2004

Compliance, Revision 1

[see: Center for Drug Evaluation and Research (CDER) at
http://www.fda.gov/cder/guidance/index.htm
or, Center for Biologics Evaluation and Research (CBER) at
http://www.fda.gov/cber/guidelines.htm]

“…This document provides guidance about computerized systems that are used to create, modify, maintain, archive, retrieve, or transmit clinical data required to be maintained and/or submitted to the Food and Drug Administration (FDA) These data form the basis for the Agency's decisions regarding the safety and effectiveness of new human and animal drugs, biological products, medical devices, and certain food and color additives. Because the data have broad public health significance, they are expected to be of the highest quality and integrity. This guidance document addresses long-standing FDA regulations concerning clinical trial records. It also addresses requirements of the Electronic Records/Electronic Signatures rule (21 CFR part 11). … Once finalized, this document will supersede the guidance of the same name issued in April 1999. Revisions will make it consistent with Agency policy as reflected in the guidance for industry on Part 11, Electronic Records; Electronic Signatures — Scope and Application, which issued in August 2003, and the Agency's international harmonization efforts. … This guidance addresses how Agency expectations and regulatory requirements regarding data quality might be satisfied where computerized systems are being used to create, modify, maintain, archive, retrieve, or transmit clinical data.”

In August 2003, the issued guidance for Part 11 provided clarification that the Agency intended to interpret the scope of part 11 narrowly and to exercise enforcement discretion with regard to Part 11 requirements for validation, audit trails, record retention, and record copying. Although this draft Guidance specifically relates to clinical trial data, the elements, concepts and requirements will have considerable overlap in detail, as well as principle, with the guidance for non-clinical laboratory studies. Thus, it is recommended that you inform yourselves and your colleagues as much as possible to allow for the best planning to satisfy compliance across your organizations.

JP Kimball
DACC Regulatory Affairs/Intersociety Liaison

Regulatory Update

Title 21 CFR Part 11 Guidance Documents Reissued

The FDA's previous re-examination of 21 CFR Part 11 as it applies to all FDA regulated products has been completed and reissued as of September 3, 2003 (21CFR Part 11\FDA 9-3-03 5667fnl.doc). On February 4, 2003 the Agency (FDA) had withdrawn all 21 CFR Part 11 Guidance documents, and then issued a new guidance on Feb. 20, 2003, to clarify exercise enforcement discretion during the re-examination of Part 11. The Agency has now completed its review and has released the revision as the final guidance, which includes Part 11 requirements for legacy systems that otherwise met predicate rule requirements and for the other provisions of 21 CFR Part 11 including validation, audit trails, record retention, and record copying. Below are selected excerpts from the new guidance for your information. Also provided in this Regulatory Update are excerpted text sections from the Sept. 3 news bulletin from the FDA.

“…This document provides guidance to persons who, in fulfillment of a requirement in a statute or another part of FDA's regulations to maintain records or submit information to FDA, have chosen to maintain the records or submit designated information electronically and, as a result, have become subject to part 11. Part 11 applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted under any records requirements set forth in Agency regulations. Part 11 also applies to electronic records submitted to the Agency under the Federal Food, Drug, and Cosmetic Act (the Act) and the Public Health Service Act (the PHS Act), even if such records are not specifically identified in Agency regulations (§ 11.1). The underlying requirements set forth in the Act, PHS Act, and FDA regulations (other than part 11) are referred to in this guidance document as predicate rules..” …"These requirements include, for example, certain provisions of the Current Good Manufacturing Practice regulations (21 CFR Part 211), the Quality System regulation (21 CFR Part 820), and the Good Laboratory Practice for Nonclinical Laboratory Studies regulations (21 CFR Part 58)"

"Under the narrow interpretation of the scope of part 11, with respect to records required to be maintained under predicate rules or submitted to FDA, when persons choose to use records in electronic format in place of paper format, part 11 would apply. On the other hand, when persons use computers to generate paper printouts of electronic records, and those paper records meet all the requirements of the applicable predicate rules and persons rely on the paper records to perform their regulated activities, FDA would generally not consider persons to be "using electronic records in lieu of paper records" under §§ 11.2(a) and 11.2(b). In these instances, the use of computer systems in the generation of paper records would not trigger part 11."

Activities to re-review your internal processes and Part 11 compliance strategies will, if not already initiated, be coming (again) to your own laboratory in the near future! Join us at the DACC LabMed Symposium on Nov. 21st in Providence, RI.

"On the first anniversary of the launch of its initiative, the Food and Drug Administration (FDA) today outlined new steps in its strategic initiative to modernize the regulation of pharmaceutical manufacturing and product quality. This initiative aims at ensuring that regulatory review, compliance and inspection policies are based on state-of-the-art pharmaceutical science, and do not impede rapid adoption of new technological advances by the pharmaceutical industry. It also promises to enhance safety and quality in drug manufacturing while increasing efficiencies. Its achievements reflect valuable advice provided to FDA through many public workshops and meetings, and written comments from experts and interested parties in academics, industry, and other groups.

"All of the major steps announced today are part of our program to increase efficiencies while maintaining and enhancing FDA’s high standards for safety in our regulation of the manufacturing of human drugs and biologics and veterinary drugs," said FDA Commissioner Dr. Mark B. McClellan, M.D., Ph.D. "This two year effort was launched last August, and under the direction of FDA’s cGMP Steering Committee, it is on track to accelerate the public health benefits from modern methods to produce more precise, effective medicines and assure their quality."

The agency has issued one final and four draft new guidances "designed to enhance the consistency and coordination of its drug quality regulatory programs, which include:

"A guidance "for FDA regulated industry on the use of electronic records and signatures"

"A draft guidance on a process for resolving disputes arising over scientific and technical issues related to pharmaceutical current good manufacturing practices (cGMP) "

"A draft guidance on the aseptic processes used in the manufacture of sterile drugs, emphasizing current science and risk-based approaches."

"A draft guidance on preparation and use of a comparability protocol for assessing chemistry, manufacturing and control changes to protein drug products and biological products".

Additionally, the agency has announced collaborations with academia, industry and other government organizations to promote innovative approaches to drug development and regulation. For more information on this and other aspects of this news release, and for comments on the draft guidances, see the respective dockets outlined in their Federal Register notices, which are available at http://www.fda.gov/cder/gmp/index.htm.